TMS & Neuromodulation · Part 4

Overview

Major depressive disorder is the condition for which transcranial magnetic stimulation (TMS) has the deepest clinical evidence and the longest U.S. treatment history. Multiple sham-controlled trials, comparative-effectiveness studies, large clinical registries, and professional guidelines support appropriately selected TMS protocols for patients who have not improved sufficiently with antidepressant treatment or who cannot tolerate it.¹²³⁴

The evidence is substantial, but it should be presented without turning a population-average result into a promise for one person. TMS can produce clinically meaningful improvement and remission, yet response varies with the patient population, protocol, outcome scale, prior treatment resistance, and whether results come from a blinded trial or open clinical practice.

The most important points are:

• Standard left-prefrontal rTMS is an established treatment. Specific devices are FDA-authorized for adults with major depression who did not achieve satisfactory improvement from prior antidepressant treatment in the current episode.¹
• Intermittent theta-burst stimulation can shorten a daily session dramatically. In the 414-participant THREE-D trial, approximately 3-minute iTBS was noninferior to approximately 37.5-minute conventional 10-Hz rTMS.³
• Accelerated TMS is now part of the U.S. regulatory landscape. One system uses functional-MRI-guided targeting and 50 sessions over five days; a May 2026 clearance permits additional defined multiple-daily-session rTMS and iTBS schedules on another platform.⁵⁶
• Benefit is meaningful but not universal. Controlled trials generally produce more conservative response and remission rates than open-label registries, and the exact scale and time point matter.³⁴
• TMS is one component of depression care. Medication, psychotherapy, sleep and substance-use treatment, medical evaluation, and safety planning may remain important.
• Urgent or life-threatening depression may require a different pathway. Imminent suicide risk, catatonia, psychotic depression, severe dehydration or malnutrition, or inability to care for oneself may require emergency evaluation, hospitalization, or electroconvulsive therapy rather than waiting for a routine outpatient TMS course.⁷

Evidence cutoff: This article reflects publicly available evidence and U.S. regulatory information through July 10, 2026. FDA authorizations are specific to the named device, age group, target, coil, and complete treatment schedule.

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Where TMS Fits in Depression Treatment

Depression treatment usually begins with a careful diagnosis, assessment of medical and psychiatric contributors, psychotherapy and/or medication, and direct evaluation of suicide risk. TMS is most commonly considered when one or more adequate antidepressant trials have not produced satisfactory improvement, when adverse effects make medication difficult to continue, or when a patient prefers a non-systemic treatment after an informed discussion.¹²

“Treatment-resistant depression” is not one perfectly standardized category. Studies and insurers differ in how many medication trials, psychotherapy trials, doses, and durations they require. The FDA label for a particular system and the eligibility rules of a particular insurer are also not identical. Clinical appropriateness should therefore not be reduced to a single administrative checklist.

TMS is often delivered in addition to existing medication or psychotherapy. It is not necessary to stop antidepressants simply because TMS begins, although every medication and any major change in dose should be reported because it can affect symptoms, tolerability, sleep, and seizure risk.

The Core Evidence: Conventional rTMS

The best-established conventional protocol uses high-frequency repetitive TMS over the left dorsolateral prefrontal cortex, usually on weekdays over several weeks. Multisite sham-controlled trials found that active treatment improved depressive symptoms more than sham in selected adults whose depression had not responded adequately to medication.¹⁸⁹

Meta-analyses across many trials support a genuine antidepressant effect, but a single summary percentage can be misleading because trials differ in:

• how much prior treatment resistance participants had;
• whether psychotic depression or bipolar disorder was excluded;
• the device, coil, target, intensity, and number of pulses;
• the number of treatment sessions and whether a taper was included;
• the rating scale used and the definition of response or remission;
• whether assessors and participants were blinded.

In depression research, response usually means at least a 50% reduction on a symptom scale. Remission means symptoms have fallen below a scale-specific threshold. Neither term guarantees that every symptom has disappeared, that function is fully restored, or that benefit will remain without ongoing care.

Shorter Daily Sessions: Intermittent Theta-Burst Stimulation

Intermittent theta-burst stimulation (iTBS) packages pulses into brief bursts modeled on naturally occurring theta rhythms. The large THREE-D randomized noninferiority trial compared approximately 3-minute iTBS with approximately 37.5-minute 10-Hz rTMS in 414 adults with treatment-resistant depression. Improvement on the Hamilton Depression Rating Scale was similar, and iTBS met the prespecified criterion for noninferiority.³

In that trial, response was approximately 49% with iTBS and 47% with 10-Hz treatment; remission was approximately 32% and 27%, respectively. Those are trial-specific outcomes, not universal rates for every device or clinic. The practical conclusion is that a properly delivered, device-authorized iTBS protocol can provide antidepressant effectiveness comparable to conventional 10-Hz treatment with a much shorter stimulation period.³¹⁰

A short stimulation time does not mean the entire appointment lasts three minutes. Positioning, symptom review, safety checks, coil alignment, and documentation still take time.

What Real-World Outcomes Add

A U.S. registry analysis of 5,010 adults treated in routine practice reported response rates ranging from approximately 58% to 83% and remission rates from approximately 28% to 62%, depending on the outcome scale.⁴ These findings show that substantial benefit is achievable outside research centers, but they should not be compared directly with a blinded trial as though the study designs were identical.

Real-world registries typically lack a sham group, may include patients who know they are receiving active treatment, and can have missing follow-up data. They are valuable for effectiveness, tolerability, and generalizability; randomized sham-controlled trials remain more reliable for estimating how much improvement is attributable specifically to the active intervention.

TMS Compared With Another Medication Strategy

The ASCERTAIN-TRD pragmatic randomized trial compared three strategies in adults with treatment-resistant depression: augmenting an antidepressant with rTMS, augmenting with aripiprazole, or switching to venlafaxine extended release (or duloxetine when venlafaxine was unsuitable). On the primary clinician-rated depression measure, rTMS augmentation produced a larger mean improvement than medication switching.¹¹

Interpretation requires restraint. The study was open-label, rater-blinded, and enrolled fewer participants than planned. The estimated response rate favored rTMS over switching, but it did not meet the study’s more stringent prespecified significance threshold; the remission difference was not statistically significant. The trial supports considering rTMS rather than reflexively cycling through medication after medication, but it does not prove that TMS is superior to every medication strategy for every patient.¹¹

Accelerated TMS: What Has Been Established

“Accelerated TMS” means more than one treatment session in a day. It does not identify one universal protocol. The target, pulses per session, intensity, number of daily sessions, interval between sessions, total dose, and treatment duration all matter.

Stanford Neuromodulation Therapy / SAINT

The FDA-cleared Magnus Neuromodulation System with SAINT technology uses structural MRI, resting-state functional MRI, individualized connectivity-based targeting, neuronavigation, high-dose iTBS, and 10 sessions per day for five days. In the initial double-blind sham-controlled trial, 29 participants received active or sham treatment; active treatment produced a substantially greater four-week reduction in depression severity.⁵¹²

A separate 2026 double-blind randomized replication enrolled 48 participants. At one month, remission occurred in 50.0% of active-treatment participants and 20.8% of sham participants. This strengthens the evidence that the complete SNT protocol has a genuine antidepressant effect, while the total randomized evidence base remains smaller than for conventional once-daily TMS.¹³

Additional Multiple-Daily-Session Protocols

In May 2026, the FDA cleared the MagVenture Accelerated TMS Therapy System for eligible adults with major depression, adding defined multiple-daily-session rTMS and iTBS schedules. Unlike SAINT, the system does not require individualized functional-connectivity targeting; the label allows standard left-prefrontal localization methods such as Beam F3, fixed-distance placement, or MRI-guided navigation, depending on the protocol and workflow.⁶

This development is clinically important, but it does not make all self-described accelerated programs equivalent. Patients should ask for the exact FDA-authorized protocol, daily schedule, intersession interval, total number of pulses, targeting method, and evidence supporting the clinic’s variation.

Does Individualized Connectivity Targeting Improve Outcomes?

Depression TMS targets are cortical entry points into distributed mood-regulation networks. Earlier observational work linked better outcomes to prefrontal targets that were more negatively connected to the subgenual cingulate.¹⁴ In a 2026 randomized trial of 40 adults receiving the same high-dose accelerated course, individualized connectivity-based targeting produced a larger median improvement at one month than Beam F3 scalp targeting.¹⁵

The trial is direct evidence that targeting can matter within that specialized accelerated setting. It does not establish that every MRI-guided approach is superior to every well-delivered standard treatment, or that structural MRI alone identifies the best functional target. A larger confirmatory trial and cost-effectiveness data would strengthen the case for routine use.

The Evidence at a Glance

When Improvement Usually Appears

Some patients notice change during the first two weeks, but many improve later. A lack of early change does not automatically mean treatment has failed. Clinicians commonly track symptoms with validated scales such as the PHQ-9, QIDS, HAM-D, or MADRS and also assess sleep, motivation, concentration, functioning, and suicide risk.

Response may emerge in stages: sleep or energy may improve before mood; family members may notice increased engagement before the patient feels “better.” Conversely, activation, agitation, worsening anxiety, mixed or manic symptoms, or increasing suicidal thoughts should be reported promptly rather than interpreted as an expected adjustment.

Durability, Tapering, Maintenance, and Retreatment

TMS is an acute-course treatment, not a guarantee of permanent remission. Some responders remain well with usual continuation care, while others relapse and benefit from another course or scheduled maintenance. Published studies use different taper and maintenance schedules, so there is no single universally proven regimen.²

A reasonable follow-up plan may include:

• continuing effective medication and/or psychotherapy;
• measurement-based visits after the acute course;
• a gradual taper when included in the device protocol or treatment plan;
• early reassessment if symptoms begin to return;
• retreatment or maintenance TMS after individualized review.

Insurance coverage for maintenance or retreatment varies and may not mirror the clinical evidence.

Safety and Tolerability in Context

The most common adverse effects are scalp discomfort, headache, and brief facial or jaw-muscle contractions during stimulation. These often lessen as treatment continues. Hearing protection is used because the coil produces a loud click. Seizure is a rare but real risk, and careful screening remains essential.²¹⁶

Established TMS protocols generally do not produce the pattern of objective cognitive decline associated with some other interventions. That is more accurate than saying TMS can never affect memory or thinking: depression itself affects cognition, individual experiences vary, and any new cognitive or neurological symptom warrants assessment.¹⁷

Who Was Not Fully Represented in Much of the Evidence?

Many pivotal depression trials excluded or underrepresented people with psychotic depression, active substance withdrawal, unstable neurological disease, high acute suicide risk, or certain implanted devices. Bipolar depression requires separate diagnostic and risk assessment because antidepressant treatments can sometimes precipitate mania or mixed symptoms. Pregnancy, older age, adolescence, and major medical comorbidity also require device-label review and individualized decision-making rather than automatic inclusion or exclusion.

Urgent safety: TMS appointments are not emergency care. Call 911 or seek immediate emergency evaluation for an imminent risk of suicide or harm, inability to maintain food or fluids, severe confusion, catatonia, psychosis, or a rapidly worsening condition. In the United States, call or text 988 for the Suicide & Crisis Lifeline.

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How to Interpret a Clinic’s Success Rate

Before accepting a headline percentage, ask:

• Was the number response, remission, or any improvement?
• Which symptom scale and threshold were used?
• Was it measured immediately after treatment or months later?
• Were all patients counted, including those who stopped early?
• Was the source a sham-controlled trial, registry, or the clinic’s internal data?
• Did the clinic use the same device, target, dose, and schedule as the cited study?

Bottom line: TMS is an evidence-based treatment for appropriately selected patients with major depression, especially after inadequate improvement or intolerance with medication. Conventional rTMS and once-daily iTBS have the broadest clinical track record. Accelerated protocols can produce faster improvement and now include more than one FDA-authorized platform, but complete protocol details and study design remain crucial. The most responsible expectation is neither pessimism nor a promise: a meaningful chance of substantial improvement, careful measurement, and a plan for what comes next.

Previous: A Brief History of TMS and Brain Stimulation
Next: Is TMS Right for Me? Patient Selection, Risks, and Safety

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References

1. U.S. Food and Drug Administration. NeuroStar TMS Therapy System: 510(k) Summary (K083538). Decision December 16, 2008.
2. Trapp NT, et al. Consensus review and considerations on TMS for the treatment of depression. Clin Neurophysiol. 2025. doi:10.1016/j.clinph.2024.12.015.
3. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D). Lancet. 2018;391:1683-1692. doi:10.1016/S0140-6736(18)30295-2.
4. Sackeim HA, Aaronson ST, Carpenter LL, et al. Clinical outcomes in a large registry of patients with major depressive disorder treated with transcranial magnetic stimulation. J Affect Disord. 2020;277:65-74. doi:10.1016/j.jad.2020.08.005.
5. U.S. Food and Drug Administration. Magnus Neuromodulation System with SAINT Technology: 510(k) Summary (K220177). September 1, 2022.
6. U.S. Food and Drug Administration. MagVenture Accelerated TMS Therapy System: 510(k) Summary (K260189). May 22, 2026.
7. National Institute of Mental Health. Brain Stimulation Therapies. Accessed July 10, 2026.
8. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208-1216. doi:10.1016/j.biopsych.2007.01.018.
9. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010;67(5):507-516. doi:10.1001/archgenpsychiatry.2010.46.
10. U.S. Food and Drug Administration. NeuroStar intermittent theta-burst labeling: 510(k) Summary (K201158). 2020.
11. Papakostas GI, Trivedi MH, Shelton RC, et al. Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment-resistant depression (ASCERTAIN-TRD). Mol Psychiatry. 2024. doi:10.1038/s41380-024-02468-x.
12. Cole EJ, Phillips AL, Bentzley BS, et al. Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022;179(2):132-141. doi:10.1176/appi.ajp.2021.20101429.
13. Kratter IH, 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. doi:10.1002/wps.70032.
14. Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012;72(7):595-603. doi:10.1016/j.biopsych.2012.04.028.
15. Taylor JJ, Kare MR, Haj-Darwish D, et al. Connectivity- vs scalp-based targeting of accelerated transcranial magnetic stimulation for depression: a randomized clinical trial. JAMA Psychiatry. Published online June 24, 2026. doi:10.1001/jamapsychiatry.2026.1100.
16. Rossi S, Antal A, Bestmann S, et al. Safety and recommendations for TMS use in healthy subjects and patient populations: expert guidelines. Clin Neurophysiol. 2021;132(1):269-306. doi:10.1016/j.clinph.2020.10.003.
17. Martin DM, McClintock SM, Forster JJ, et al. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: a systematic review and meta-analysis. Depress Anxiety. 2017;34(11):1029-1039. PMID:28543994.

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