Accelerated Neuromodulation: SAINT and Other Fast-Track TMS Protocols

Introduction

For over two decades, transcranial magnetic stimulation (TMS) has offered hope to patients with treatment-resistant depression (TRD). Its noninvasive nature, favorable safety profile, and steadily accumulating evidence base have made it a cornerstone intervention. Yet, one of its most persistent limitations has been time to response. Conventional TMS protocols, whether 10 Hz stimulation or intermittent theta-burst stimulation (iTBS), typically require daily sessions over four to six weeks, with many patients only achieving remission late in the course. For individuals in acute crisis, such as those with suicidality or severe functional impairment, this timeline can feel frustratingly slow.

In response, researchers have explored ways to accelerate neuromodulation. The most prominent development is the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which condenses six weeks of iTBS into five days of intensive, individualized treatment. Early reports suggest strikingly high remission rates, far exceeding conventional TMS, while also delivering relief within days rather than weeks. Variants such as SNT (Stanford Neuromodulation Therapy) and other accelerated iTBS approaches are now being studied globally.

The scientific and clinical communities, however, remain divided. Enthusiasm stems from the potential to redefine the trajectory of depression treatment, but caution is warranted. Most positive findings come from single-center studies with limited sample sizes, raising questions about durability and reproducibility. Methodological issues, including sham controls, blinding, and expectancy effects, continue to be debated. Moreover, implementing accelerated schedules presents logistical and economic barriers that few health systems are currently equipped to overcome.

This review examines the emerging landscape of accelerated neuromodulation, focusing on efficacy, durability, and targeting strategies, while scrutinizing safety, regulatory status, and real-world feasibility. The aim is not only to assess whether SAINT and related protocols herald a true paradigm shift, but also to identify the unanswered questions that will determine their place in psychiatry’s future.

Efficacy Compared with Standard Protocols

The benchmark for TMS efficacy in treatment-resistant depression has long been defined by conventional 10 Hz left dorsolateral prefrontal cortex (DLPFC) protocols and, more recently, FDA-cleared intermittent theta burst stimulation (iTBS). Both approaches achieve remission rates of roughly 25–35% in large randomized controlled trials, with most responses emerging after four to six weeks of treatment. These outcomes, while significant, underscore the need for approaches that are not only more potent but also more rapid. Accelerated neuromodulation protocols attempt to meet this challenge by condensing multiple iTBS sessions into a single day. The flagship example, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), delivers up to ten iTBS sessions daily over five consecutive days, with stimulation sites chosen using functional connectivity MRI (fcMRI). In the pivotal open-label study by Cole and colleagues (2020), remission rates exceeded 70% within one week of treatment, far surpassing conventional benchmarks. Notably, many patients reported symptom relief within the first two to three days, a pace previously unseen with neuromodulation.

Replication efforts, though smaller, have echoed these findings. Pilot studies of Stanford Neuromodulation Therapy (SNT) and other accelerated iTBS schedules have demonstrated response rates in the 50–65% range, with remission rates consistently higher than those observed in standard TMS cohorts. A randomized controlled pilot study by Zhou et al. (2023) compared accelerated iTBS with sham and found significantly greater reductions in depression scores, though the sample size (n≈30) limits generalizability.

Durability remains a key question. In SAINT follow-ups, many patients maintained remission for three to six months, but relapse rates gradually increased thereafter, mirroring patterns seen in standard TMS. Maintenance strategies, whether through booster sessions or integration with pharmacotherapy, are being explored but lack systematic study.

Taken together, the evidence suggests that accelerated protocols may shift the efficacy curve upward and deliver responses far faster than existing FDA-cleared options. Yet the field is still in its infancy. Larger, multicenter, sham-controlled trials will be needed to confirm whether these dramatic early results represent a genuine breakthrough or an artifact of highly selective samples and intensive trial settings.

Evidence Quality: Sham Controls and Replication

The enthusiasm surrounding accelerated TMS protocols is built on a foundation that, while promising, is not yet robust. The majority of SAINT and SNT trials to date have been conducted at single centers, most often Stanford, with sample sizes typically under 50 participants. These limitations raise concerns about selection bias, site expertise, and reproducibility.

Sham-controlled data provide a more cautious picture. In the randomized pilot study by Zhou et al. (2023), accelerated iTBS significantly outperformed sham, but the trial enrolled only 29 participants, and its design could not fully exclude expectancy effects. Maintaining blinding in TMS studies is notoriously difficult, as participants may detect differences in scalp sensation or treatment intensity. For accelerated protocols, with their extremely high session frequency, the challenge is even greater. Patients may infer assignment simply from the intensity of their daily schedule, complicating interpretation.

Efforts at replication are underway. A multicenter trial registered as NCT03068715 is designed to test accelerated TMS in a more diverse patient population and across multiple treatment settings. These data will be critical in addressing whether SAINT’s dramatic remission rates can be reproduced outside the Stanford environment.

Another gap lies in durability of benefit. Most sham-controlled studies have focused on acute outcomes at the one- or two-week mark. Longer-term relapse prevention remains underexplored, and follow-up data from single centers, while encouraging, cannot substitute for larger trials.

Finally, generalizability remains uncertain. Most accelerated studies recruit highly motivated patients with unipolar major depression. Evidence for bipolar depression, comorbid psychosis, or non-responders to standard TMS is minimal. Without trials in these groups, claims of broad applicability are premature.

To date, the quality of evidence is best described as early but fragile. Positive findings have generated justified excitement, yet without large, rigorously blinded, multicenter replications, the risk of overestimating efficacy remains high. The next phase of research will determine whether accelerated neuromodulation is a paradigm shift or a promising but niche innovation.

Targeting: The Role of fcMRI Guidance

One of the most distinctive features of the SAINT protocol is its reliance on functional connectivity MRI (fcMRI) to identify the optimal stimulation site within the dorsolateral prefrontal cortex (DLPFC). Unlike traditional scalp-based heuristics, such as the “5-cm rule” or the Beam F3 method, fcMRI targeting allows clinicians to select the DLPFC subregion most anticorrelated with the subgenual anterior cingulate cortex (sgACC), a network thought to mediate mood regulation. Evidence suggests this refinement may account for much of SAINT’s unusually high remission rates. In the original Stanford studies, fcMRI targeting consistently produced outcomes superior to historical data using scalp heuristics. Patients whose stimulation sites were less strongly anticorrelated with the sgACC were also more likely to relapse, underscoring the importance of connectivity-based precision.

Still, the approach is not without drawbacks. fcMRI is costly, technically demanding, and not universally available. Many community TMS centers lack access to advanced neuroimaging, limiting scalability. Even in research settings, there is debate over whether individualized targeting provides sufficient incremental benefit to justify its resource intensity.

Hybrid strategies may emerge as a pragmatic compromise. Structural MRI–based neuronavigation, for instance, offers improved anatomical accuracy over scalp heuristics, without the logistical hurdles of fcMRI. Ongoing trials will clarify whether fcMRI targeting truly delivers a step change in outcomes, or whether more accessible methods can achieve comparable efficacy in real-world practice.

At present, fcMRI remains the most scientifically compelling but least practical element of accelerated TMS protocols. Its future will depend on whether replication studies confirm its critical role, or whether it proves to be an enhancer rather than a prerequisite for success.

Safety Profile and Risks

Safety remains a central consideration as accelerated TMS protocols push stimulation intensity far beyond traditional schedules. Standard TMS has long been regarded as low risk, with the most common adverse effects being mild scalp discomfort, transient headaches, or fatigue. Early studies of SAINT and related accelerated approaches have reported similar tolerability profiles, even with multiple sessions delivered in a single day. Concerns about seizure risk are natural, given the density of stimulation. To date, no seizures have been reported in SAINT trials, though the sample sizes remain modest, and vigilance is warranted as protocols scale. Equally important is the possibility of hypomania or mania induction in patients with bipolar depression. Case reports suggest this risk, while rare, is real and requires careful screening and monitoring.

Cognitive side effects have been minimal. Unlike electroconvulsive therapy (ECT), accelerated TMS does not appear to impair memory or executive function, and in some studies, patients have shown subtle improvements in attention or processing speed, possibly reflecting relief of depressive symptoms rather than a direct cognitive benefit.

Overall, the short-term safety record is reassuring, but long-term effects are unknown. Intensive dosing raises theoretical concerns about neuroplasticity beyond targeted circuits, which only extended follow-up and larger samples will clarify. For now, accelerated TMS appears safe within research settings, though broader clinical adoption will demand robust surveillance systems.

Implementation and Real-World Barriers

The promise of accelerated TMS collides with the realities of clinical practice. SAINT, in its original form, requires up to ten sessions per day for five consecutive days, with each session separated by carefully timed intervals. Delivering this schedule demands clinic space, multiple TMS devices, and dedicated staff available from early morning to evening. Few outpatient centers are currently equipped to operate at such intensity.

Reimbursement adds another layer of complexity. At present, payers typically cover FDA-cleared TMS protocols, namely daily 10 Hz stimulation or standard iTBS. Accelerated schedules, including SAINT, remain experimental and thus uncovered by most insurers. For patients, this translates into significant out-of-pocket costs, effectively restricting access to those with financial means or participation in research trials. Workforce capacity also presents a challenge. Accelerated protocols increase the time burden on technicians and clinicians, potentially leading to burnout or high staffing costs. Training requirements may expand if precision targeting with fcMRI or neuronavigation becomes standard. Without systemic support, adoption is likely to remain concentrated in academic centers.

Despite these hurdles, patient demand may drive innovation. Individuals facing severe depression, particularly those in acute crisis, are understandably drawn to treatments that promise rapid relief. Clinics may experiment with modified accelerated protocols, for example, fewer daily sessions or extended schedules over two weeks, to balance feasibility with efficacy.

Ultimately, implementation will hinge on regulatory recognition and payer adaptation. If large trials validate SAINT or similar approaches, insurers will face pressure to integrate them into coverage frameworks. Until then, real-world deployment will remain sporadic, highlighting the gap between research promise and practical delivery.

Conclusion

Accelerated neuromodulation represents one of the most ambitious frontiers in contemporary psychiatry. Protocols like SAINT promise something long sought but rarely achieved: rapid remission in treatment-resistant depression, often within days. For patients whose lives are constrained by the slow trajectory of standard therapies, the possibility of near-immediate relief is transformative.

Yet, the field is still in its early stages. Most of the striking results come from single-center studies, with small samples and methodological challenges that limit certainty. Without large, multicenter, sham-controlled trials, it is premature to declare accelerated TMS a paradigm shift. Replication will be the test that determines whether current enthusiasm translates into durable clinical practice.

Implementation issues add further complexity. Intensive scheduling, workforce demands, and lack of reimbursement remain major barriers. Precision targeting with fcMRI guidance, while scientifically compelling, risks reinforcing inequities if it proves essential but remains accessible only in resource-rich centers. Still, the momentum is undeniable. Accelerated TMS protocols push the boundaries of what neuromodulation can deliver, and they have opened a conversation about whether psychiatric treatments can and should operate on faster timelines. The coming years will decide whether SAINT becomes a standard of care, or a fascinating but fleeting chapter in the evolution of brain stimulation.

References

1. Cole, E. J., Phillips, A. L., Bentzley, B. S., et al. (2020). Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression. American Journal of Psychiatry, 177(8), 716–726. https://doi.org/10.1176/appi.ajp.2019.19070720

2. Williams, N. R., & Sudheimer, K. D. (2023). State of the science on accelerated neuromodulation protocols for depression. Neuropsychopharmacology, 48(3), 489–502. https://www.nature.com/articles/s41386-023-01599-z

3. Zhou, W., Loo, C. K., & Brunoni, A. R. (2023). Accelerated intermittent theta burst stimulation for major depression: A randomized controlled pilot study. BMC Psychiatry, 23, 5470. https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-023-05470-9

4. U.S. National Library of Medicine. (2025). Multicenter trial of accelerated TMS for depression (NCT03068715). ClinicalTrials.gov. Retrieved from https://www.clinicaltrials.gov/study/NCT03068715