Second Double-Blind RCT Confirms SAINT® TMS Remission Rates for Treatment-Resistant Depression

Treatment-resistant depression (TRD) affects more than 30% of individuals diagnosed with major depressive disorder (MDD), a condition affecting over 280 million people worldwide.¹ For many patients and their families, TRD can mean years of trying medications and therapies without meaningful relief. 

TRD is most frequently defined as an insufficient response to at least two adequate trials of antidepressant medications.² For patients and families who have spent years trying multiple treatments without relief, new therapeutic options are urgently needed. A recent study³ published in World Psychiatry provides encouraging new evidence and confirms the findings of an earlier RCT and multiple open label trials that investigated the efficacy of SAINT® (Stanford Accelerated Intelligent Neuromodulation Therapy), also referred to as SNT (Stanford Neuromodulation Therapy), in treating hard-to-treat depression.⁴ 

The earlier clinical research that first introduced SAINT generated considerable attention in the mental health community. In initial studies, patients with severe treatment-resistant depression experienced unusually high remission rates after a brief five-day treatment course—results that were far higher than those typically seen with conventional TMS protocols, which often require daily treatment over six weeks. The new randomized clinical trial was designed to determine whether those promising results could be replicated in a larger, rigorously controlled study.

“The new study replicated the previous finding that SAINT is effective in TRD and demonstrated this in a larger number of patients,” says Dr. Ian Kratter, clinical assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, and lead author of the study. “The consistency of the findings from this trial, which is the largest SAINT randomized controlled trial to date, with the initial trial’s results, is significant because the effectiveness of novel treatments is all too often not replicated when tested again.”  

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Understanding SAINT and How it Works

The prefrontal cortex, a core region for emotional and cognitive processing and regulation, is thought to play a key role in the etiology of depression.⁵ Dysfunction of the prefrontal cortex “is thought to be a key aspect of what causes depression.”⁵  Brain stimulation interventions are often considered for patients with TRD who have not responded to first-line pharmacological and psychotherapeutic treatments. SAINT is an FDA-cleared treatment that stimulates the brain by delivering rapid magnetic pulses to a targeted region of the patient’s prefrontal cortex.⁶ 

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Inside the New Randomized Clinical Trial

Researchers at the Stanford Brain Stimulation Lab (BSL) examined “the antidepressant effects of SAINT and investigated its underlying neurophysiological mechanisms” on patients with TRD.³ They recruited 53 individuals with TRD; 48 participants were randomized to active (N=24) or sham (N=24) SNT. The SAINT treatment protocol begins by acquiring both structural and functional MRI scans of the brain.⁵ The functional MRI reveals insights into the communication between different brain regions.⁵ Participants were treated with 1,800 pulses of intermittent theta-burst stimulation per session at 90% resting motor threshold depth-adjusted to the personalized functional target.³ Participants received ten sessions per day (18,000 pulses/day) for 5 consecutive days (90,000 total pulses), with a 50-minute inter-session interval between same-day treatment sessions.³ 

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Study Results: Meaningful Improvements in Many Patients

One outcome of the study was “the rate of response” (defined as ≥50.0% improvement from baseline) 1-month after treatment using the MADRS. The response rates for active and sham SAINT were 54.2% and 25.0%, respectively.”³ At one-month post-treatment, remission rates (the percentage of participants who become largely symptom-free) were 50% for active participants and only 20.8% for sham.³ The findings are similar to the initial trial’s remission rate of 46.2 percent one-month post-treatment.⁴

Replication in rigorous randomized controlled trials is widely considered one of the strongest indicators that a treatment effect is real and reproducible. As such, replicating these results in a second randomized controlled trial is particularly significant because treatments do not always demonstrate the same effectiveness when studied again in larger or more rigorous trials. “In depression research, it is actually quite common for treatments to struggle to clearly separate from sham treatment in randomized controlled trials,” says Dr. Brandon Bentzley, co-founder and CMO of Salma Health and an author of the study. “Many antidepressant medications, as well as newer therapies, have produced mixed results in clinical trials, with some failing to show a statistically significant difference from sham in their primary analysis. For example, esketamine (Spravato) did not statistically separate from sham at one month in most of its randomized trials, even with continued treatment, and other TMS treatments have faced similar challenges in their pivotal studies under the intent-to-treat analysis. Against that backdrop, the ability of SAINT to demonstrate a statistically significant separation from sham treatment and then replicate those results in a second randomized controlled trial is particularly noteworthy.”

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What Brain Activity Revealed About How SAINT Works

Researchers also analyzed “the neurophysiological effects of SAINT via EEG recorded pre-and post-treatment.”³ They examined data from a subset of an initial trial and the current one. The EEG results indicated that SAINT-induced changes in brain activity correlated with improvements in mood. Specifically, they found that participants who experienced a greater reduction in beta activity in the left anterior cingulate cortex (L-ACC) after SAINT also showed greater improvements in depression symptoms both immediately after treatment and one month later. Beta activity refers to a type of brain wave associated with active, alert and focused mental states in the brain. Beta activity in the cingulate cortex is particularly relevant in the context of depression because it effectively tracks depressive states.^7,8 Also noteworthy, patients with higher baseline beta activity in the L-ACC before treatment tended to benefit more from SAINT.

“The SAINT treatment specifically decreased beta power in the left anterior cingulate cortex, a brain region that plays an important role in regulating emotion and mood. We observed that the greater the reduction in the beta range on the EEG, the more the individual's condition improved," says Dr. Kratter.

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What These Findings May Mean for People

SAINT may offer a non-pharmacological treatment alternative with a shorter course, fewer risks and minimal side effects. Its effectiveness underscores the potential of neuroscience-informed principles to refine existing treatments and inspire new ones. This finding regarding EEG suggests a novel possibility: using a simple, affordable EEG test to predict which patients are most likely to benefit from SAINT before treatment begins. Clinicians might one day be able to prioritize SAINT for patients with an elevated L-ACC beta signature, potentially improving outcomes and optimizing the use of limited resources. 

Other study results indicate that for some patients, remission has lasted from several months to years after a single five-day course of treatment.⁵ Other patients have required periodic "tune-up" treatments to maintain remission for a year.⁵  These tune-ups are often thought of as similar to annual dental visits for teeth cleaning. 

Further research is needed, but SAINT continues to show promise and offers hope for people who have spent years—even decades—trying various treatments with no real relief. In time, researchers hope that SAINT will become a front-line treatment option for patients with TRD.

To learn more about SAINT, read our blog posts “What Is TMS? A Non-Invasive, FDA-Cleared Treatment for Depression”⁹ and “Precision Neuromodulation for Treatment-Resistant Depression.”¹⁰ If you or someone you know is struggling with TRD, contact Salma Health. We make it easy to have a 15-minute Care Options Call, connect with our care team, complete a comprehensive intake, or schedule online. We meet you where you are and build care around your needs. Schedule your first appointment today and experience a higher standard of brain care—grounded in science, clarity, and continuity.

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_References:

1. _{GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204–1222.  doi: 10.1016/S0140-6736(20)30925-9}
2. _{Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163:1905-17 doi: 10.1176/ajp.2006.163.11.1905.}
3. _{Kratter IH, Austelle CW, Lissemore JI, et al. Stanford neuromodulation therapy for treatment-resistant depression: a randomized controlled trial confirming efficacy, and an EEG study providing insight into mechanism of action and a potentially predictive biomarker of efficacy. World Psychiatry. 2026;25(1):105–116 https://doi.org/10.1002/wps.70032}
4. _{Cole EJ, Phillips AL, Bentzley BS et al. Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022;179:132-41. doi: 10.1176/appi.ajp.2021.20101429}
5. _{Rogers K. First on CNN: Noninvasive brain treatment for depression proves helpful. CNN, January 20, 2026. https://www.cnn.com/2026/01/15/health/saint-tms-depression-therapy-wellness}
6. _{Magnus Medical. https://www.magnusmedical.com}
7. _{Xiao J, Adkinson JA, Myers J, et al. Beta activity in human anterior cingulate cortex mediates reward biases. Nat Commun. 2024 Jul 15;15:5528. doi: 10.1038/s41467-024-49600-7}
8. _{Alagapan S, Choi KS, Heisig S, et al. Cingulate dynamics track depression recovery with deep brain stimulation. Nature. 2023;622:130–138. https://doi.org/10.1038/s41586-023-06541-3}
9. _{The Salma Health Team. What Is TMS? A Non-Invasive, FDA-Cleared Treatment for Depression. Salma Health, February 1, 2026.}
10. _{Bentzley B. Precision Neuromodulation for Treatment-Resistant Depression. Salma Health, November 4, 2025.}

_{a.  MADRS, which stands for Montgomery–Åsberg Depression Rating Scale, is a standardized questionnaire clinicians use to measure the severity of depression in patients. Composed of 10 items, it assesses symptoms such as sadness, tension, sleep disturbance, appetite changes, concentration difficulties, and suicidal thoughts. Each item is scored from 0 to 6, yielding a maximum total score of 60, with higher scores indicating greater depression severity.}

_{b.  The L-ACC is an area known to play a central role in emotion regulation and previously implicated in the mechanisms of brain stimulation therapies.}