Major Depressive DisorderPhase 1NCT04142320
Closed-loop Optimized rTMS for Depression
A Phase 1 study testing Neuronavigated rTMS in people with Major Depressive Disorder, run by Stanford University at 1 site in United States.
Trial summary
Targeted and individualized treatments for mental health disorders are critically needed. Repetitive transcranial magnetic stimulation (rTMS) represents the front-line of new and innovative approaches to normalizing dysfunctional brain networks in those with mental illness. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Neuronavigated rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 41 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2021to 10 Jul 2025
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women, ages 18 to 65
- Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales
- Right-handed
- No current or history of neurological disorders
- No seizure disorder or risk of seizures
- No use of PRN medication within 48 hours of the scheduled study appointment
Who cannot join
- Those with a contraindication for MRIs (e.g. implanted metal)
- Any unstable medical condition
- History of head trauma with loss of consciousness
- History of seizures
- Neurological or uncontrolled medical disease
- Active substance abuse
Show all 10Show fewer
- Diagnosis of psychotic or bipolar disorder
- A prior history of ECT or rTMS failure
- Currently taking medications that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, lithium)
- Currently pregnant or breastfeeding
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized, Cross-over, Placebo-controlled Trial to Determine Target Engagement and Dose Response of Optimized Closed-loop rTMS for Medication-resistant Depression
Targeted and individualized treatments for mental health disorders are critically needed. Repetitive transcranial magnetic stimulation (rTMS) represents the front-line of new and innovative approaches to normalizing dysfunctional brain networks in those with mental illness. rTMS is FDA-approved for depression and obsessive-compulsive disorder with clinical trials underway for PTSD and addiction, among others. However, remission rates are suboptimal and ideal stimulation parameters are unknown. We recently completed a randomized, double blind clinical trial and a depression severity biomarker that predicts clinical outcome. The overarching goal of this study is to develop the first broadly generalizable platform for real-time biomarker monitoring and personalized rTMS treatment. We plan to recruit patients with medication-resistant depression and in perform a four-phase, cross-over, double-blind, placebo-controlled trial to 1) identify how standard and optimized rTMS patterns engage the depression severity biomarker, and 2) determine the dose-response of these rTMS patterns. Findings from this study will provide the basis for a double-blind, randomized clinical trial comparing rTMS optimized to the individual against standard rTMS.
Read the detailed description
Nearly 50% of all Americans will suffer from a mental health disorder during their lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), are increasingly used to normalize dysfunctional brain circuits in these disorders. Mechanistically, rTMS is thought to work by changing the synaptic strength of neurons, referred to as brain plasticity. Despite the variety of disorders targeted and significant between-patient heterogeneity, rTMS is currently applied in a manner that is one-size-fits-all (without any individual optimization of the stimulation pattern) and open-loop (fixed schedule of stimulation pattern, with no measurement or adjustment during rTMS). We believe that the response rate of rTMS for depression, which is at present <50%, can be improved through personalized brain stimulation that enhances target engagement and maximizes plasticity. To personalize brain stimulation, one must (1) measure and monitor brain changes in real-time; (2) determine the optimal stimulation patterns for inducing brain changes; (3) develop adaptive treatments to drive desired changes on an individual patient-specific level over time. Such personalization of brain stimulation will increase our mechanistic understanding of brain plasticity to improve efficacy in non-responders to standard treatments.
The primary goals of my research program are to (1) discover brain biomarkers that predict progression to clinical remission, and (2) develop closed-loop treatment algorithms that optimize these biomarkers and improve clinical outcomes. We will focus on depression as it is the leading cause of disability worldwide and and medications are ineffective or not tolerated for close to half of these patients. Leveraging my previous work, we propose three stages of development of personalized brain stimulation using single pulses of TMS combined with electroencephalography (TMS-EEG) to generate a causal measurement of brain state that can easily be translated to the clinic. The TMS-EEG depression severity biomarker that I recently discovered occurs 30 milliseconds after administering a TMS test pulse (p30) in the fronto-parietal network (FPN), a region implicated in depression. The degree of suppression of this p30 signal predicted clinical outcome in depressed patients following rTMS treatment. Additionally, a single stimulation session was sufficient to suppress the p30 during and for 30 minutes after stimulation. This work indicates that p30 suppression can be monitored in real-time and has the potential to support empiric treatment optimization.
Findings from this study will provide the basis for a double-blind, randomized clinical trial of closed-loop rTMS against standard rTMS.
- Conditions
- Major Depressive Disorder
- Being tested
- Neuronavigated rTMS, sham rTMS
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neuronavigated rTMSDevice
Delivers patterned magnetic stimulation using MRI-guided neuronavigation.
sham rTMSDevice
Delivers placebo magnetic stimulation
| Study group | Role | What they receive |
|---|---|---|
| Personalized rTMS | Experimental | Participants received personalized rTMS using MRI-guided neuronavigation to target the dorsolateral prefrontal cortex (dlPFC). Intermittent theta burst stimulation (iTBS) consisted of 600 pulses delivered over approximately 3.5 minutes at 110% of the participant's resting motor threshold. Participants were monitored throughout each stimulation session for adverse events and side effects. Receives: Device: Neuronavigated rTMS |
| Sham rTMS | Experimental | Participants may receive sham rTMS using MRI-guided neuronavigation in a crossover design. Sham stimulation was designed to mimic active stimulation while maintaining participant blinding. Participants were monitored throughout each stimulation session for adverse events and side effects. Receives: Device: sham rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Early-local TMS-evoked Potential (EL-TEP)
TMS-EEG was used to measure the peak-to-peak amplitude of the TMS-evoked potential between 20-60 milliseconds after single TMS pulses in the left frontoparietal region. Changes in the TMS-evoked EEG response were quantified in decibels (dB) relative to baseline. Measurements were obtained before and after the rTMS intervention to assess neurophysiologic changes associated with target engagement.
Measured: Baseline: ~1 hour before first intervention; Pre-intervention: ~1-15 min before first TBS; Post-intervention: ~1-15 min after last TBS, ~100 min after first TBS.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Oct 2019
- Study start1 Jun 2021
- Primary completion10 Jul 2025
- Study completion10 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Corey Keller, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04142320
- Sponsor's protocol ID
- 60980-1
- Other IDs
- R01MH126639
- Status last verified
- Sep 2026
- First submitted
- 17 Oct 2019
- Last updated
- 29 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized, Cross-over, Placebo-controlled Trial to Determine Target Engagement and Dose Response of Optimized Closed-loop rTMS for Medication-resistant Depression
- ClinicalTrials.gov ID
- NCT04142320
- Acronym / sponsor ID
- 60980-1
- Conditions
- Major Depressive Disorder
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 1 Jun 2021 (actual)
- Primary completion
- 10 Jul 2025 (actual)
- Study completion
- 10 Jul 2025 (actual)
- First posted
- 29 Oct 2019 (actual)
- Results
- Posted 29 Sep 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Targeted and individualized treatments for mental health disorders are critically needed. Repetitive transcranial magnetic stimulation (rTMS) represents the front-line of new and innovative approaches to normalizing dysfunctional brain networks in those with mental illness. rTMS is FDA-approved for depression and obsessive-compulsive disorder with clinical trials underway for PTSD and addiction, among others. However, remission rates are suboptimal and ideal stimulation parameters are unknown. We recently completed a randomized, double blind clinical trial and a depression severity biomarker that predicts clinical outcome. The overarching goal of this study is to develop the first broadly generalizable platform for real-time biomarker monitoring and personalized rTMS treatment. We plan to recruit patients with medication-resistant depression and in perform a four-phase, cross-over, double-blind, placebo-controlled trial to 1) identify how standard and optimized rTMS patterns engage the depression severity biomarker, and 2) determine the dose-response of these rTMS patterns. Findings from this study will provide the basis for a double-blind, randomized clinical trial comparing rTMS optimized to the individual against standard rTMS.
Detailed description
Nearly 50% of all Americans will suffer from a mental health disorder during their lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), are increasingly used to normalize dysfunctional brain circuits in these disorders. Mechanistically, rTMS is thought to work by changing the synaptic strength of neurons, referred to as brain plasticity. Despite the variety of disorders targeted and significant between-patient heterogeneity, rTMS is currently applied in a manner that is one-size-fits-all (without any individual optimization of the stimulation pattern) and open-loop (fixed schedule of stimulation pattern, with no measurement or adjustment during rTMS). We believe that the response rate of rTMS for depression, which is at present <50%, can be improved through personalized brain stimulation that enhances target engagement and maximizes plasticity. To personalize brain stimulation, one must (1) measure and monitor brain changes in real-time; (2) determine the optimal stimulation patterns for inducing brain changes; (3) develop adaptive treatments to drive desired changes on an individual patient-specific level over time. Such personalization of brain stimulation will increase our mechanistic understanding of brain plasticity to improve efficacy in non-responders to standard treatments.
The primary goals of my research program are to (1) discover brain biomarkers that predict progression to clinical remission, and (2) develop closed-loop treatment algorithms that optimize these biomarkers and improve clinical outcomes. We will focus on depression as it is the leading cause of disability worldwide and and medications are ineffective or not tolerated for close to half of these patients. Leveraging my previous work, we propose three stages of development of personalized brain stimulation using single pulses of TMS combined with electroencephalography (TMS-EEG) to generate a causal measurement of brain state that can easily be translated to the clinic. The TMS-EEG depression severity biomarker that I recently discovered occurs 30 milliseconds after administering a TMS test pulse (p30) in the fronto-parietal network (FPN), a region implicated in depression. The degree of suppression of this p30 signal predicted clinical outcome in depressed patients following rTMS treatment. Additionally, a single stimulation session was sufficient to suppress the p30 during and for 30 minutes after stimulation. This work indicates that p30 suppression can be monitored in real-time and has the potential to support empiric treatment optimization.
Findings from this study will provide the basis for a double-blind, randomized clinical trial of closed-loop rTMS against standard rTMS.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Personalized rTMS | Experimental | Device: Neuronavigated rTMSParticipants received personalized rTMS using MRI-guided neuronavigation to target the dorsolateral prefrontal cortex (dlPFC). Intermittent theta burst stimulation (iTBS) consisted of 600 pulses delivered over approximately 3.5 minutes at 110% of the participant's resting motor threshold. Participants were monitored throughout each stimulation session for adverse events and side effects. |
| Sham rTMS | Experimental | Device: sham rTMSParticipants may receive sham rTMS using MRI-guided neuronavigation in a crossover design. Sham stimulation was designed to mimic active stimulation while maintaining participant blinding. Participants were monitored throughout each stimulation session for adverse events and side effects. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Men and women, ages 18 to 65
- Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales
- Right-handed
- No current or history of neurological disorders
- No seizure disorder or risk of seizures
Key exclusion criteria (10 listed)
- Those with a contraindication for MRIs (e.g. implanted metal)
- Any unstable medical condition
- History of head trauma with loss of consciousness
- History of seizures
- Neurological or uncontrolled medical disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neuronavigated rTMSDelivers patterned magnetic stimulation using MRI-guided neuronavigation. | Device | Personalized rTMS |
| sham rTMSDelivers placebo magnetic stimulation | Device | Sham rTMS |
Primary outcome
Change in Early-local TMS-evoked Potential (EL-TEP)
Time frame: Baseline: ~1 hour before first intervention; Pre-intervention: ~1-15 min before first TBS; Post-intervention: ~1-15 min after last TBS, ~100 min after first TBS.
TMS-EEG was used to measure the peak-to-peak amplitude of the TMS-evoked potential between 20-60 milliseconds after single TMS pulses in the left frontoparietal region. Changes in the TMS-evoked EEG response were quantified in decibels (dB) relative to baseline. Measurements were obtained before and after the rTMS intervention to assess neurophysiologic changes associated with target engagement.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Neuronavigated rTMS in people with Major Depressive Disorder, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Sep 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Early-local TMS-evoked Potential (EL-TEP) (time frame: Baseline: ~1 hour before first intervention; Pre-intervention: ~1-15 min before first TBS; Post-intervention: ~1-15 min after last TBS, ~100 min after first TBS.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2026.