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    Evidence Library

    Clinical Research Behind Advanced Depression Treatments

    This library summarizes peer-reviewed and authoritative research related to treatments offered by Neuro Wellness TMS Centers of America, including SAINT® TMS, conventional TMS, and SPRAVATO® (esketamine). For every study we list the design, population, main finding, and important limitations, with a direct link to the original source. This is an educational resource, not medical advice.

    Medically reviewed by Daniel Pietras, MD — Board-Certified Psychiatrist. Last updated September 21, 2026.

    Key Takeaways

    • SAINT®'s 79% remission figure comes from a double-blind, sham-controlled randomized trial of 29 analyzed patients (Cole et al., Am J Psychiatry, 2022). It is not a guarantee of individual outcome.
    • Conventional TMS has the largest evidence base, including a 301-patient sham-controlled trial and a 307-patient real-world study reporting ~58% response and ~37% remission among completers.
    • SPRAVATO® (esketamine) is FDA-approved for treatment-resistant depression based on Phase 3 sham-controlled trials; it is administered under a REMS monitoring program.
    • Study results describe the populations studied. Different study designs (sham-controlled vs. open-label vs. registry) produce different types of evidence and are not directly comparable.
    • Neuro Wellness TMS Centers of America offers treatments within their FDA-authorized indications. We do not conduct clinical trials.

    SAINT® Research

    SAINT® (Stanford Accelerated Intelligent Neuromodulation Therapy) was developed at Stanford University and is delivered on the Magnus Neuromodulation System. The FDA cleared the device under 510(k) K220177 in September 2022 for adults with major depressive disorder who have not achieved satisfactory improvement from prior antidepressant medication in the current episode.

    Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial

    Cole EJ, Phillips AL, Bentzley BS, et al. · American Journal of Psychiatry, 2022

    Population:
    29 adults with treatment-resistant depression (analyzed; 32 enrolled)
    Study design:
    Double-blind, sham-controlled randomized controlled trial
    Main finding:
    78.6% of the active treatment group met remission criteria at 4 weeks, compared to 13.3% of the sham group.
    Limitations:
    Small sample from a single site; follow-up limited to 4 weeks; no head-to-head comparison with standard TMS.
    View original source

    Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression

    Cole EJ, Stimpson KH, Bentzley BS, et al. · American Journal of Psychiatry, 2020

    Population:
    21 adults with treatment-resistant depression
    Study design:
    Open-label (no sham control)
    Main finding:
    19 of 21 completers (90.5%) met remission criteria after 5 days of treatment.
    Limitations:
    No sham comparison group; small sample; single site; open-label design can introduce expectancy bias.
    View original source

    FDA clearance: Magnus Neuromodulation System with SAINT Technology, 510(k) K220177, cleared September 2022. FDA Breakthrough Device Designation. View FDA 510(k) record

    Conventional TMS Research

    Repetitive transcranial magnetic stimulation (rTMS) has the largest evidence base among the treatments offered at Neuro Wellness. The first TMS device was FDA-cleared for depression in 2008. The studies below represent the pivotal sham-controlled trial, a major real-world registry, and the THREE-D trial that established theta burst stimulation as non-inferior to standard 10 Hz TMS.

    Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression

    O'Reardon JP, Solvason HB, Janicak PG, et al. · Biological Psychiatry, 2007

    Population:
    301 adults with major depressive disorder
    Study design:
    Multisite randomized sham-controlled trial
    Main finding:
    Active TMS was superior to sham, with a statistically significant improvement in depression scores.
    Limitations:
    Short-term acute treatment phase; response and remission rates were modest; long-term durability not established in this trial.
    View original source

    Transcranial Magnetic Stimulation (TMS) for Major Depression: A Multisite, Naturalistic, Observational Study

    Carpenter LL, Janicak PG, Aaronson ST, et al. · Depression and Anxiety, 2012

    Population:
    307 patients in real-world clinical practice
    Study design:
    Naturalistic observational study (no control group)
    Main finding:
    Approximately 58% response and 37% remission on clinician-rated scales among patients completing treatment.
    Limitations:
    No control group; open-label; reflects patients who completed treatment, not all who started; clinician-rated outcomes may differ from patient-rated.
    View original source

    Effectiveness of Theta Burst Versus High-Frequency Repetitive Transcranial Magnetic Stimulation in Patients with Depression (THREE-D)

    Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. · Lancet, 2018

    Population:
    414 adults with treatment-resistant depression
    Study design:
    Randomized non-inferiority trial (two active arms, no sham)
    Main finding:
    Intermittent theta burst stimulation (iTBS) was non-inferior to 10 Hz rTMS, with similar symptom improvement and side effects.
    Limitations:
    Compared two active treatments without a sham arm; results apply to once-daily treatment, not accelerated schedules.
    View original source

    SPRAVATO® (Esketamine) Research

    SPRAVATO® (esketamine) nasal spray is FDA-approved for treatment-resistant depression and for depressive symptoms in adults with acute suicidal ideation or behavior. It is administered under a REMS (Risk Evaluation and Mitigation Strategy) program with mandatory in-office monitoring. The entries below link to the pivotal published trial and the FDA-approved prescribing information.

    Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined with a New Oral Antidepressant in Treatment-Resistant Depression

    Daly EJ, Singh JB, Fedgchin M, et al. · JAMA Psychiatry, 2018

    Population:
    Adults with treatment-resistant depression who had not responded to 2–5 antidepressant trials
    Study design:
    Phase 3 randomized double-blind sham-controlled trial
    Main finding:
    Esketamine plus a new oral antidepressant showed greater symptom improvement than the nasal sham plus a new oral antidepressant at day 28.
    Limitations:
    Modest effect size; dissociation and other adverse effects were common; long-term safety data came from open-label extension studies.
    View original source

    SPRAVATO® (esketamine) Prescribing Information — FDA-Approved Labeling

    Janssen Pharmaceuticals, Inc. / U.S. FDA · FDA Drug Labeling (BLA 211243), 2019 (updated 2025)

    Population:
    Adults with treatment-resistant depression; adults with MDD and acute suicidal ideation/behavior
    Study design:
    FDA regulatory review of pivotal trials
    Main finding:
    FDA-approved for treatment-resistant depression (as monotherapy or with an oral antidepressant) and for depressive symptoms in adults with acute suicidal ideation/behavior (with an oral antidepressant). Administered under a REMS program.
    Limitations:
    Approval is specific to these indications; other uses are off-label. Common effects include dissociation, sedation, and blood pressure elevation.
    View original source

    Accelerated TMS: FDA-Cleared vs. Investigational Protocols

    "Accelerated TMS" is a broad term for any TMS schedule delivering more than one session per day. It is important to distinguish the FDA-cleared accelerated protocol from off-label or investigational schedules.

    ProtocolFDA StatusKey Evidence
    SAINT® (Magnus System)FDA-cleared (K220177)Double-blind sham-controlled RCT + open-label study (Cole et al., 2020 & 2022)
    Other accelerated schedules on conventional devicesOff-labelVaried small studies; no FDA-reviewed protocol; evidence base is smaller and heterogeneous
    Once-daily iTBS (theta burst)FDA-cleared (once-daily)THREE-D trial (Blumberger et al., 2018) — non-inferiority to 10 Hz rTMS

    For a full breakdown of FDA-cleared vs. investigational uses across all conditions, see our Research & Investigational Treatments page.

    How to Read This Research

    Clinical research uses different study designs, and each has different strengths. A double-blind, sham-controlled randomized trial is the strongest type of evidence because it isolates whether the treatment itself causes improvement. An open-label study, where everyone receives the real treatment, cannot separate the treatment's effect from placebo or expectancy.

    A registry or naturalistic study counts real-world patients who completed treatment, which reflects clinical practice but includes no comparison group. Response and remission figures from different study designs are not directly comparable.

    Every study has limitations — small samples, single-site recruitment, short follow-up, or the absence of a control group. We list the key limitations for each study so you can weigh the evidence honestly. If you have questions about what a study means for your situation, discuss it with a qualified clinician.

    Frequently Asked Questions

    Where can I read the original SAINT clinical trials?

    The two primary SAINT publications are Cole et al. (2022) in the American Journal of Psychiatry — the double-blind sham-controlled trial — and Cole et al. (2020), the open-label study. Both are linked above with direct URLs to PubMed. We encourage patients and families to read the original research and discuss it with a qualified clinician.

    Does the 79% remission rate mean I will go into remission?

    No. The 79% figure comes from the active treatment group in a small, single-site randomized trial of 29 analyzed patients. It describes the group studied, not any individual's likelihood. Individual results vary, and no treatment for depression guarantees remission.

    Is the research on TMS for PTSD or bipolar depression as strong as for depression?

    No. TMS for major depressive disorder has multiple randomized sham-controlled trials and FDA clearance. TMS for PTSD and bipolar depression has smaller, mixed studies and no FDA-cleared device indication. Those uses are off-label.

    What is the difference between a sham-controlled trial and an open-label study?

    A sham-controlled trial includes a placebo (sham) group that receives a fake treatment, so researchers can isolate whether the real treatment itself is causing improvement. An open-label study has no placebo group — everyone receives the real treatment — so expectancy and placebo effects cannot be separated from the treatment's effect.

    Does Neuro Wellness conduct clinical trials?

    No. Neuro Wellness TMS Centers of America is a treatment provider, not a research institution. We offer treatments within their FDA-authorized indications. If you are interested in participating in research, search ClinicalTrials.gov or ask your clinician about ongoing trials at academic medical centers.

    If you are thinking about harming yourself, call or text 988 (Suicide & Crisis Lifeline) in the U.S., or go to the nearest emergency room.

    Related Resources

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