Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive neuromodulation therapy for major depressive disorder (MDD) and related conditions, addressing unmet needs for patients with treatment resistance or intolerance to conventional medications. Over the past decade, clinical research has refined rTMS protocols, expanded target sites, and validated long-term outcomes, solidifying its role in modern psychiatry. This article synthesizes key findings from recent clinical trials and studies, highlighting breakthroughs in protocol design, efficacy data, and practical applications.

The Evolution of rTMS Protocols: From Single-Site to Dual-Target and Accelerated Approaches

Traditional rTMS protocols primarily targeted the left dorsolateral prefrontal cortex (dlPFC) with high-frequency stimulation over 4–6 weeks, but limited efficacy and delayed response have spurred innovation. A landmark randomized controlled trial (RCT) by Zhao et al. (2025) introduced a sequential dual-site accelerated protocol, targeting the left dlPFC and dorsomedial prefrontal cortex (dmPFC) over 4 consecutive days (4 sessions/day, 16 total sessions). This approach delivered rapid results—significant Montgomery-Åsberg Depression Rating Scale (MADRS) reductions were observed as early as day 4, with 57.69% response rate and 38.46% remission rate at week 4, compared to 23.08% and 15.38% in the sham group. Notably, over 85% of responders maintained remission for 6 months, demonstrating sustained efficacy (Zhao et al., 2025).

The dual-site strategy addresses MDD’s neural network heterogeneity by modulating distinct circuits: increased dlPFC-frontoparietal connectivity (linked to cognitive control) and decreased dmPFC-limbic connectivity (associated with emotion regulation; Zhao et al., 2025). This contrasts with single-site stimulation, which often fails to target overlapping or complementary networks. For treatment-resistant depression (TRD), McDonald et al. (2011) showed that optimizing session quantity improves outcomes—patients requiring >5 weeks of active left dlPFC stimulation achieved higher remission rates (30.5%) than those limited to shorter courses, highlighting the need for personalized duration (McDonald et al., 2011).

Accelerated protocols, defined by multiple daily sessions, have also gained traction. The Zhao et al. (2025) study used 50-minute inter-session intervals, aligning with research indicating 50–90 minutes optimizes synaptic plasticity and cumulative effects (Kramar et al., 2012 as cited in Zhao et al., 2025). This approach reduces treatment burden, making rTMS accessible to patients with work or geographic constraints—a critical advantage over standard 4–6 week regimens.

Efficacy Across Depression Subtypes: From Unipolar to Bipolar Depression

rTMS efficacy extends beyond unipolar MDD to bipolar depression, a subtype historically challenging to treat due to mood destabilization risks. Koutsomitros et al. (2022) tested a low-pulse protocol (1000 pulses/session, 20 total sessions, 20,000 total pulses) targeting the left dlPFC in bipolar II depression patients. The study reported a 61% remission rate post-treatment and 78% at 1-month follow-up, with no hypomanic switches—addressing a key safety concern (Koutsomitros et al., 2022). This supports meta-analytic findings that high-frequency left dlPFC stimulation is effective for bipolar depression (Nguyen et al., 2020 as cited in Koutsomitros et al., 2022).

For TRD, maintenance rTMS is critical for preventing relapse. Yamazaki et al. (2023) designed a 12-month maintenance protocol (weekly for 6 months, biweekly for 6 months) and found that combining rTMS with pharmacotherapy reduced relapse rates compared to pharmacotherapy alone. A meta-analysis by Senova et al. (2019 as cited in Yamazaki et al., 2023) confirmed this: 6-month response rates were 61.1% with maintenance rTMS versus 38.5% without. These data underscore that rTMS is not just an acute intervention but a viable long-term strategy (Yamazaki et al., 2023).

Not all studies show uniform success, however. Lingeswaran (2011) conducted a small RCT (n=23) of 6 sessions/week over 2 weeks and found no significant differences in HDRS or MADRS scores between active and sham groups. Limitations included small sample size, uneven group distribution, and low statistical power, highlighting the importance of adequate sample sizes and optimized protocols (Lingeswaran, 2011).

Safety and Tolerability: A Well-Established Profile

rTMS maintains a favorable safety profile across studies. Zhao et al. (2025) reported no severe adverse events, with the most common issue being stimulation site discomfort (38.46% in active vs. 7.69% in sham groups), which resolved spontaneously. Headache and dizziness were rare and mild, consistent with previous findings (Chen et al., 2020 as cited in Zhao et al., 2025). For bipolar patients, Koutsomitros et al. (2022) noted only one dropout due to irritability, with no seizures or mood switches—confirming safety in this vulnerable population (Koutsomitros et al., 2022).

McDonald et al. (2011) observed similar tolerability in TRD patients, with headache (26%) and stimulation site discomfort (18%) as the most frequent adverse events, and no seizures or long-term sequelae. This aligns with guidelines confirming rTMS as a low-risk alternative to electroconvulsive therapy (ECT), which carries cognitive side effect risks (Lefaucheur et al., 2020 as cited in multiple studies).

Future Directions: Personalization and Accessibility

The next frontier for rTMS lies in personalized medicine. Zhao et al. (2025) identified baseline functional connectivity biomarkers—lower dlPFC-lateral orbitofrontal cortex (latOFC) connectivity and higher dmPFC-subgenual anterior cingulate cortex (sgACC) connectivity—that predicted treatment response. This opens avenues for pre-treatment imaging to select optimal candidates (Zhao et al., 2025). Additionally, scalp-based targeting (used in Zhao et al., 2025 and McDonald et al., 2011) offers cost-efficiency and generalizability, making rTMS accessible to clinics without neuronavigation technology.

For maintenance therapy, Yamazaki et al. (2023) emphasize the need for large-scale RCTs to validate weekly/biweekly protocols, while Koutsomitros et al. (2022) call for placebo-controlled trials to confirm low-pulse protocols in bipolar depression. Addressing these gaps will further solidify rTMS as a first-line option for diverse depressive populations.

Conclusion

Repetitive transcranial magnetic stimulation has evolved from a experimental therapy to a evidence-based treatment for depression, with advancements in dual-site targeting, accelerated protocols, and maintenance strategies. Key studies by Zhao et al. (2025), McDonald et al. (2011), Yamazaki et al. (2023), Koutsomitros et al. (2022), and Lingeswaran (2011) demonstrate its efficacy across unipolar, bipolar, and treatment-resistant subtypes, with a consistent safety profile. As research continues to refine personalization and accessibility, rTMS is poised to transform depression care—offering hope for patients failed by conventional treatments.

References

• Koutsomitros, T., van der Zee, K. T., Evagorou, O., Schuhmann, T., Zamar, A. C., & Sack, A. T. (2022). A Different rTMS Protocol for a Different Type of Depression: 20.000 rTMS Pulses for the Treatment of Bipolar Depression Type II. Journal of Clinical Medicine, 11(18), 5434. https://pmc.ncbi.nlm.nih.gov/articles/PMC9505040/
• Lingeswaran, A. (2011). Repetitive Transcranial Magnetic Stimulation in the Treatment of depression: A Randomized, Double-blind, Placebo-controlled Trial. Indian Journal of Psychological Medicine, 33(1), 35–44. https://pmc.ncbi.nlm.nih.gov/articles/PMC3195152/
• McDonald, W. M., Durkalski, V., Ball III, E. R., Holtzheimer III, P. E., Pavlicova, M., Lisanby, S. H., Avery, D., Anderson, B. S., Nahas, Z., Zarkowski, P., Sackeim, H. A., & George, M. S. (2011). Improving the antidepressant efficacy of transcranial magnetic stimulation: Maximizing the number of stimulations and treatment location in treatment resistant depression. Depression and Anxiety, 28(11), 973–980. https://pmc.ncbi.nlm.nih.gov/articles/PMC4413508/
• Yamazaki, R., Matsuda, Y., Oba, M., Oi, H., & Kito, S. (2023). Maintenance repetitive transcranial magnetic stimulation (rTMS) therapy for treatment-resistant depression: a study protocol of a multisite, prospective, non-randomized longitudinal study. BMC Psychiatry, 23(1), 437. https://pmc.ncbi.nlm.nih.gov/articles/PMC10273734/
• Zhao, Y.-J., Xiang, S., Chen, R., Ding, Q., Geng, R., Wang, Y., Li, Y., Li, H., Wang, Y., Cui, H., Huang, Y., Feng, J., Liu, W., & Voon, V. (2025). A sequential dual-site repetitive transcranial magnetic stimulation for major depressive disorder: A randomized clinical trial. Cell Reports Medicine, 6(10), 102402. https://pmc.ncbi.nlm.nih.gov/articles/PMC12629819/